23_ 11_2012-01-00003-00000030
`
`-7-
`
`solution comprises no more than 50 particles ~1 Oµm in diameter per ml. In one
`embodiment, the ophthalmic solution comprises no more than 2 particles ~50µm in
`diameter per ml, no more than 5 particles ~25µm in diameter per ml and no more than 50
`particles ~1 Oµm in diameter per ml. In one embodiment, a syringe according to the
`invention meets USP789.
`In one embodiment the syringe has low levels of silicone oil
`sufficient for the syringe to meet USP789.
`
`5
`
`· VEGF Antagonists
`
`Antibody VEGF antagonists
`
`10
`
`VEGF is a well-characterised signal protein which stimulates angiogenesis. Two antibody
`VEGF antagonists have been approved for human use. namely ranibizumab (Lucentis®}
`and bevacizuniab (Avastin®).
`
`Non-Antibody VEGF antagonists
`
`15
`
`20
`
`25
`
`30
`
`In one aspect of the invention, the non-antibody VEGF antagonist is an immunoadhesin.
`One such immuoadhesin is aflibercept (Eylea®), which has recently been approved for
`human use and is also known as VEGF-trap (Holash et al. (2002) PNAS USA 99: 11393-
`98; Riely & Miller (2007) Clin Cancer Res 13:4623-7s). Aflibercept is the preferred non(cid:173)
`antibody VEGF antagonist for use with the invention. Aflibercept is a recombinant human
`soluble VEGF receptor fusion protein consisting of portions of human VEGF receptors 1
`and 2 extracellular domains fused to the Fe portion of human lgG1. It is a dimeric
`glycoprotein with a protein molecular weight of 97 kilodaltons (kDa) and contains
`glycosylation, constituting an additional 15% of the total molecular mass, resulting in a
`total molecular weight of 115 kDa. It is conveniently produced as a glycoprotein by
`expression in recombinant CHO k1 cells. Each monomer can have the following amino
`acid sequence (SEQ ID NO: 1 ):
`
`SDTGRPFVEMYSEIPEIIHMTEGRELVIPCRVTSPNITVTLKKFPLDTLIPDGKRIIWDSRK
`GFIISNATYKEIGLLTCEATVNGHL YKTNYLTHRQTNTIIDWLSPSHGIELSVGEKLVLNC
`TARTELNVGIDFNWEYPSSKHQHKKL VNRDLKTQSGSEMKKFLSTL TIDGVTRSDQGL Y
`TCAASSGLMTKKNSTFVRVHEKDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTP
`EVTCVWDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRWSVLTVLHQDWL
`NGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDEL TKNQVSL TCLVKGFY
`PSDIAVEWESNGQPENNYKTTPPVLDSDGSFFL YSKL TVDKSRWQQGNVFSCSVMHE
`ALHNHYTQKSLSLSPG
`
`and disulfide bridges can be formed between residues 30-"19, 124-185, 246-306 and
`352-410 within each monomer, and between residues 211-211 and 214-214 between the
`35 monomers.
`
`Regeneron Exhibit 1002.0381
`
`

`

`-
`23_ 11_2012-01-00003-00000031
`
`-8-
`
`5
`
`in pre-clinical
`immunoadhesin currently
`Another non-antibody VEGF antagonist
`development is a recombinant human soluble VEGF receptor fusion protein similar to
`VEGF-trap containing extracellular ligand-binding domains 3 and 4 from VEGFR2/KDR,
`and domain 2 from VEGFR1/Flt-1; these domains are fused to a human lgG Fe protein
`fragment (Li et al., 2011 Molecular Vision 17:797-803). This antagonist binds to isoforms
`VEGF-A, VEGF-B and VEGF-C. The molecule is prepared using two different production
`processes resulting in different glycosylation patterns on the final proteins. The two
`glycoforms are referred to as KH902 (conbercept) and KH906. The fusion protein can
`have the following amino acid sequence (SEQ ID N0:2):
`
`10 MVSYWDTGVLLCALLSCLLLTGSSSGGRPFVEMYSEIPEI IHMTEGRELVIPCRVTSPNIT
`VTLKKFPLDTLIPDGKRIIWDSRKGFIISNA TYKEIGLL TCEA TVNGHL YKTNYL THRQTNT
`IIDWLSPSHGIELSVGEKLVLNCTARTELNVGIDFNWEYPSSKHQHKKLVNRDLKTQSG
`SEMKKFLSTL TIDGVTRSDQGL YTCMSSGLMTKKNSTFVRVHEKPFVAFGSGMESLVE
`ATVGERVRLPAKYLGYPPPEIKWYKNGIPLESNHTIKAGHVLTIMEVSERDTGNYTVILTN
`15 PISKEKQSHWSL WYVPPGPGDKTHTCPLCPAPELLGGPSVFLFPPKPKDTLMISRTPE
`VTCVVVDVSHEDPEVKFNVVYVDGVEVHNAKTKPREEQYNSTYRWSVLTVLHQDWLN
`GKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDEL TKNQVSL TCLVKGFYP
`SDIAVEWESNGQPENNYKA TPPVLDSDGSFFL YSKL TVDKSRWQQGNVFSCSVMHEA
`LHNHYTQKSLSLSPGK
`
`20
`
`and, like VEGF-trap, can be present as a dimer. This fusion protein and related
`molecules are further characterized in EP1767546.
`
`Other non-antibody VEGF antagonists include antibody mimetics (e.g. Affibody®
`molecules, affilins. affitins, anticalins, avimers. Kunitz domain peptides, and monobodies)
`with VEGF antagonist activity. This includes recombinant binding proteins comprising an
`ankyrin repeat domain that binds VEGF-A and prevents it from binding to VEGFR-2. One
`example for such a molecule is DARPin® MP0112. The ankyrin binding domain may
`have the following amino acid sequence (SEQ ID NO: 3):
`
`25
`
`GSDLGKKLLEAARAGQDDEVRILMANGADVNTADSTGWTPLHLAVPWGHLEIVEVLLK
`YGADVNAKDFQGWTPLHLAMIGHQEIVEVLLKNGADVNAQDKFGKTAFDISIDNGNED
`LAEILQKM
`
`30
`
`Recombinant binding proteins comprising an ankyrin repeat domain that binds VEGF-A
`to VEGFR-2 are described
`in more detail
`in
`and prevents
`it
`from binding
`W02010/060748 and W02011/135067.
`
`Further specific antibody mimetics with VEGF antagonist activity are the 40 kD pegylated
`anticalin PRS-050 and the monobody angiocept (CT-322).
`
`35
`
`Regeneron Exhibit 1002.0382
`
`

`

`23 _ 11 _2012-01-00003-00000032
`
`23.-l l-2012-:0.l-00003-00000032
`
`- t
`f4't,
`
`-9-
`
`The afore-mentioned non-antibody VEGF antagonist may be modified to further improve
`their pharmacokinetic properties or bioavailability. For example, a non-antibody VEGF
`antagonist may be chemi~lly modified (e.g., pegylated) to extend its in vivo half-life.
`Alternatively or in addition, it may be modified by glycosylation or the addition of further
`glycosylation sites not present in the protein sequence of the natural protein from which
`the VEGF antagonist was derived.
`
`Variants of the above-specified. VEGF antagonists that have improved characteristics for
`the desired application may be produced by the addition or deletion of amino acids.
`Ordinarily, these amino acid sequence variants will have an amino acid sequence having
`at least 60% amino acid sequence identity with the amino acid sequences of SEQ ID
`NO: 1, SEQ ID NO: 2 or SEQ ID NO: 3, preferably at least 80%, more preferably at least
`85%, more preferably at least 90%, and most preferably· at least 95%, including for
`example, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%,
`93%, 94%, 95%, 96%, 97%, 98%, 99%, and 100%. Identity or homology with respect to
`this sequence is defined herein as the percentage of amino acid residues in the
`candidate sequence that are identical with SEQ ID NO: 1, SEQ ID NO: 2 or SEQ ID NO:
`3, after aligning the sequences and introducing gaps, if necessary, to achieve the
`maximum percent sequence identity, and not considering any conservative substitutions
`as part of the sequence identity.
`
`Sequence identity can be determined by standard methods that are commonly used to
`compare the similarity in position of the amino acids of two polypeptides. Using a
`computer program such as BLAST or FASTA, two polypeptides are aligned for optimal
`matching of their respective amino acids (either along the full length of one or both
`sequences or along a pre-determined portion of one or both sequences). The programs
`provide a default opening penalty and a default gap penalty, and a scoring matrix such
`as PAM 250 [a standard scoring matrix; see Dayhoff et al., in Atlas of Protein Sequence
`and Structure, vol. 5, supp. 3 (1978)] can be used in conjunction with the computer
`program. For example, the percent identity can then be calculated as: the total number
`of identical matches multiplied by 100 and then divided by the sum of the length of the
`longer sequence within the matched span and the number of gaps introduced into the
`longer sequences in order to align the two sequences.
`
`Preferably, the non-antibody VEGF ant~gonist of the invention binds to VEGF via one or
`more protein domain(s) that are not derived from the antigen-binding domain of an
`antibody. The non-antibody VEGF antagonist of
`the
`invention are preferably
`proteinaceous, but may
`include modifications
`that are non-proteinaceous (e.g.,
`pegylation, glycosylation).
`
`5
`
`10
`
`15
`
`20
`
`25
`
`30
`
`35
`
`Regeneron Exhibit 1002.0383
`
`

`

`23_ 11_2012-01-00003-00000033
`
`Therapy
`
`-10-
`
`5
`
`10
`
`15
`
`20
`
`The syringe of the invention may be used to treat an ocular disease, including but not
`. limited to choroidal neovascularisation, age-related macular degeneration (both wet and
`dry forms), macular edema secondary to retinal vein occlusion (RVO) including both
`branch RVO (bRVO) and central RVO (cRVO), choroidal neovascularisation secondary
`to pathologic myopia (PM), diabetic macular edema (DME), diabetic retinopathy, and
`proliferative retino pathy.
`
`Thus the invention provides a method of treating a patient suffering from of an ocular
`disease selected
`from choroidal neovascularisation, wet age-related macular
`degeneration, macular edema secondary to retinal vein occlusion (RVO) including both
`branch RVO (bRVO) and central RVO (cRVO), choroidal neovascularisation secondary
`to pathologic myopia (PM), diabetic macular edema (DME), diabetic retinopathy, and
`proliferative retinopathy, comprising the step of administering an ophthalmic solution to
`the patient using a pre-filled syringe of the invention. This method preferably further
`comprises an initial priming step in which the physician depresses the plunger of the pre(cid:173)
`filled syringe to align the pre-determined part of the stopper with the priming m~rk.
`
`In one embodiment, the invention provides a method of treating an. ocular disease
`selected from choroidal neovascularisation, wet age-related macular degeneration,
`macular edema secondary to retinal vein occlusion (RVO) including both branch RVO
`(bRVO) and central RVO (cRVO), choroidal neovascularisation secondary to pathologic
`myopia (PM), diabetic macular edema (DME), diabetic retinopathy, and proliferative
`retinopathy, comprising administering a non-antibody VEGF antagonist with a pre-filled
`syringe of the invention, wherein the patient has previously received treatment with an
`antibody VEGF antagonist.
`
`25
`
`Kits
`
`Also provided are kits comprising the pre-filled syringes of the invention. In one
`embodiment, such a kit comprises a pre-filled syringe of the invention in a blister pack.
`The blister pack may itself be sterile on the inside. In one embodiment, syringes
`according to the invention may be placed inside such blister packs prior to· undergoing
`sterilisation, for example terminal sterilisation.
`
`Such a kit may further comprise a needle for administration of the VEGF antagonist. If
`the VEGF antagonist is to be administered intravitreally, it is typical to use a 30-gauge x
`% inch needle, though 31-gauge and 32-gauge needles may be used. For intravitreal
`administration, 33-gauge or 34-gauge needles could alternatively be used. Such kits may
`further comprise instructions for use. In one embodiment, the invention provides a carton
`
`30
`
`35
`
`Regeneron Exhibit 1002.0384
`
`

`

`23_ 11_2012-01-00003-00000034
`
`containing a pre-filled syringe according to the invention contained within a blister pack, a
`needle and optionally instructions for administration.
`
`- 11 -
`
`Sterilisation
`
`As noted above, a terminal sterilisation process may be used to sterilise the syringe and
`such a process may use a known process such as an ethylene oxide or a hydrogen
`peroxide sterilisation process. Needles to be used with the syringe may be sterilised by
`the same method, as may kits according to the invention.
`
`The package is exposed to the sterilising gas until the outside of the syringe is sterile.
`Following such a process, the outer surface of the syringe may remain sterile (whilst in
`its blister pack) for up to 6 months, 9 months, 12 months, 15 months, 18 months or
`longer. In one embodiment, less than one syringe in a million has detectable microbial
`presence on the outside of the syringe after 18 months of storage. In one embodiment,
`the pre-filled syringe has been sterilised using EtO with a Sterility Assurance Level of at
`least 10-6. In one embodiment, the pre-filled syringe has been sterilised using hydrogen
`peroxide with a Sterility Assurance Level of at least 10-6. Of course, it is a requirement
`that significant amounts of the sterilising gas should not enter the variable volume
`chamber of the syringe. The term "significant amountsn as used herein refers to an
`amount of gas that would cause unacceptable modification of the ophthalmic solution
`within the variable volume chamber. In one embodiment, the sterilisation process causes
`s_10%
`(preferably s_5%, ~3%, s_1%) alkylation of the VEGF antagonist.
`In one
`embodiment, the pre-filled syringe has been sterilised using EtO, but the outer surface of
`the syringe has s_1ppm, preferably s_0.2ppm EtO residue. In one embodiment, the pre(cid:173)
`filled syringe has been sterilised using hydrogen peroxide, but the outer surface of the
`syringe has s_1 ppm, preferably s_0.2ppm hydrogen peroxide residue.
`In another
`embodiment, the pre-filled syringe has been sterilised asing EtO, and the total EtO
`residue found on the outside of the syringe and inside of the blister pack is ~0.1 mg. In
`another embodiment, the pre-filled syringe has been sterilised using hydrogen peroxide,
`· and the total hydrogen peroxide residue found on the outside of the syringe and inside of
`the blister pack is s_0.1mg.
`
`5
`
`10
`
`15
`
`20
`
`25
`
`30
`
`General
`
`The term "comprisingD means "includingn as well as "consistingn e.g. a composition
`"comprisingn X may consist exclusively of X or may include something additional e.g. X +
`Y.
`
`35
`
`The term "about• in relation to a numerical value x means, for example, x±10%.
`
`Regeneron Exhibit 1002.0385
`
`(. I
`
`,
`
`\
`
`

`

`23_ 11_2012-01-00003-00000035
`
`-12-
`
`5
`
`References to a percentage sequence identity between two amino acid sequences
`means that, when aligned, that percentage of amino acids are the same in comparing the
`two sequences. This alignment and the percent homology or sequence identity can be
`determined using software programs known in the art, for example those described in
`section 7.7.18 of Cu"ent Protocols in Molecular Biology (F.M. Ausubel et al., eds., 1987)
`Supplement 30. A preferred alignment is determined by the Smith-Waterman homology
`search algorithm using an affine gap search with a gap open penalty of 12 and a gap
`extension pe-nalty of 2, BLOSUM matrix of 62. The Smith-Waterman homology search
`algorithm is disclosed in Smith & Waterman (1981) Adv. Appl. Math. 2: 482-489
`
`10 BRIEF DESCRIPTION OF THE FIGURES
`
`Figure 1 shows a side view of a syringe
`
`Figure 2 shows a cross section of a top down view of a syringe
`
`Figure 3 shows a view of a plunger
`
`Figure 4 shows a cross section though a plunger
`
`15
`
`Figure 5 shows a stopper
`
`MODES FOR CARRYING OUT THE INVENTION
`
`The invention will now be further described, by way of example only, with reference to
`the drawings.
`
`20
`
`Figure 1 shows a view from a side of a syringe 1 comprising a body 2, plunger 4,
`backstop 6 and a sealing device 8.
`
`25
`
`Figure 2 shows a cross section through the syringe 1 of Figure 1 from above. The
`syringe 1 is suitable for use in an ophthalmic injection. The syringe 1 comprises a body
`2, a stopper 1 O and a plunger 4. The syringe 1 extends along a first axis A. The body 2
`comprises an outlet 12 at an outlet end 14 and the stopper 10 is arranged within the
`body 2 such that a front surface 16 of the stopper 10 and the body 2 define a variable
`volume chamber 18.
`The variable volume chamber 18 contains an
`injectable
`medicament 20 comprising an ophthalmic solution comprising a VEGF antagonist such
`as ranibizumab. The injectable fluid 20 can be expelled though the outlet 12 by
`30 movement of the stopper 1 O towards the outlet end 14 thereby reducing the volume of
`the variable volume chamber 18. The plunger 4 comprises a plunger contact surface 22
`at a first end 24 and a rod 26 extending between the plunger contact surface 22 and a
`rear portion 25. The plunger contact surface 22 is arranged to contact the stopper 10,
`such that the plunger 4 can be used to move the stopper 10 towards the outlet end 14 of
`
`Regeneron Exhibit 1002.0386
`
`

`

`23_ 11_2012-01-00003-00000036
`
`- 13 -
`
`the body 2. Such movement reduces the volume of the variable volume chamber 18 and
`causes fluid therein to be expelled though the outlet.
`
`The backstop 6 is attached to the body 2 by coupling to a terminal flange 28 of the body
`2. The backstop 6 includes sandwich portion 30 which is adapted to substantially
`
`5
`
`sandwich at least some of the terminal flange 28 of the body 2. The backstop 6 is
`adapted to be coupled to the body 2 from the side by leaving one side of the backstop 6
`open so that the backstop 6 can be fitted to the syringe 2.
`
`10
`
`15
`
`20
`
`25
`
`30
`
`The body 2 defines a substantially cylindrical bore 36 which has a bore radius. The rod
`26 comprises a rod shoulder 32 directed away from the outlet end 14. The rod shoulder
`32 extends from to a rod shoulder. radius from the first axis A which is· such that it is
`slightly less than the bore radius so that the shoulder fits within the bore 36. The
`backstop 6 includes a backstop shoulder 34 directed towards the outlet end 14. The
`shoulders 32, 34 are configured to cooperate to substantially prevent movement of the
`rod 26 away from the outlet end 14 when the backstop shoulder 34 and rod shoulder 32
`are in contact. The backstop shoulder 34 extends from outside the bore radius to a
`radius less than the rod shoulder radius so that the rod should~r 32 cannot pass the
`backstop shoulder 34 by moving along the first axis A. In this case the rod shoulder 32 is
`substantially disc, or ring, shaped and the backstop shoulder 34 includes an arc around a
`rear end 38 of the body 2.
`
`The backstop 6 also includes two finger projections 40 which extend in opposite
`directions away from the body 2 substantially perpendicular to the first axis A to facilitate
`manual handling of the syringe 1 during use.
`
`In this example the syringe comprises a 0.5ml body 2 filled with between about 0.1 and
`0.3 ml of an injectable medicament 20 comprising a 1 Omg/ml injectable solution
`comprising ranibizumab. The syringe body 2 has an internal diameter of about between
`about 4.5mm and 4.8mm, a length of between about 45mm and 50mm.
`
`The plunger 4 and stopper 10 will be described in more detail with reference to later
`figures.
`
`Figure 3 shows a perspective view of the plunger 4 of Figure 1 showing the plunger
`
`contact surface 22 at the first end 24 of the plunger 4. The rod 26 extends from the first
`end 24 to the rear portion 25. The rear portion 25 includes a disc shaped flange 42 to
`facilitate user handling of the device. The flange 42 provides a larger surface area for
`contact by the user than a bare end of the rod 26.
`
`Figure 4 shows a cross section though a syringe body 2 and rod 26. The rod 26 includes
`four longitudinal ribs 44 and the angle between the ribs is 90°.
`
`35
`
`-· · - · · · - - -
`
`Regeneron Exhibit 1002.0387
`
`

`

`23_ 11_2012-01-00003-00000037
`
`l -
`
`/) ·-·,
`
`5
`
`10
`
`- 14 -
`
`Figure 5 shows a detailed view of a stopper 10 showing a conical shaped front surface
`16 and three circumferential ribs 52,54,56 around a substantially cylindrical body 58.
`The axial gap between the. first rib 52 and the last rib 56 is ab_out 3mm. The rear surface
`60 of the stopper 1 O includes a substantially central recess 62. The central recess 62
`includes an initial bore 64 having a first diameter. The initial bore 64 leading from the
`rear surface 60 into the stopper 1 O to an inner recess 66 having a second diameter, the
`second diameter being larger than the first diameter.
`
`Stopper forces
`
`0.5ml syringes siliconised with <100µg silicone oil, filled with Lucentis, comprising one of
`two different stopper designs were tested for maximal and average break out and slide
`force. Prior to testing, 30Gx 0.5" needles were attached to the syringes. The testing was
`carried out at a stopper speed of 190mm/min over a travel length of 10.9mm.
`
`Stopper design 1
`
`Stopper design 2
`
`Batch A
`
`Batch B
`
`Batch C
`
`Batch D Batch E
`
`Break
`Average of 1 O 2.-2N
`loose force syringes
`of syringes
`
`2.5N
`
`Max
`individual
`value
`
`2.3N
`
`U:~N
`
`2.1N
`
`2.5N
`
`2.5N
`
`2.3N
`
`2.6N
`
`2.7N
`
`Sliding
`force
`
`Average of 1 0 3.1N
`syringes
`
`3.2N
`
`3.1N
`
`4.1N
`
`4.6N
`
`3.5N
`
`3.5N
`
`3.6N
`
`4.7N
`
`4.8N
`
`Max
`individual
`value
`
`15
`
`For both stopper designs, average and maximum break out force remained below 3N.
`For both stopper designs, average and maximum sliding force remained below 5N.
`
`It will be understood that the invention has been described by way of example only and
`modifications may be made whilst remaining within the scope and spirit of the invention.
`
`20
`
`Regeneron Exhibit 1002.0388
`
`

`

`23_ 11 _2012-01-00003-00000038
`
`Claims
`
`- 15 -
`
`5
`
`10
`
`15
`
`1.
`
`A pre-filled syringe, the syringe comprising a body, a stopper and a plunger, the
`body comprising an outlet at an outlet end and the stopper being arranged within
`the body such that a front surface of the stopper and the body define a variable
`volume chamber from which a fluid can be expelled though the outlet, the plunger
`comprising a plunger contact surface at a first end and a rod extending between
`the plunger contact surface and a rear portion, the plunger contact surface
`arranged to contact the stopper, such that the plunger can be used to force the
`stopper towards the outlet er:td of the body, reducing the volume of the variable
`volume chamber, characterised in that the fluid is an ophthalmic solution which
`comprises a VEGF-antagonist, wherein
`
`(a) the syringe has a nominal maximum fill volume of between about 0.5ml and
`about 1ml,
`
`(b) the syringe is filled with between about 0.15ml and about 0.175ml of said VEGF
`antagonist solution which comprises a dosage volume of about 0.05ml of said
`VEGF antagonist solution,
`
`(c) the syringe barrel comprises less than about SOOµg silicone oil,
`
`(d) the VEGF antagonist solution comprises no more than 2 particles .:::,SOµm in
`diameter per ml, and
`
`20
`
`(e) the VEGF antagonist is the antibody VEGF antagonist bevacizumab.
`
`2.
`
`25
`
`30
`
`A pre-filled syringe, the syringe comprising a body, a stopper and a plunger, the
`body comprising an outlet at an outlet end and the stopper being arranged within
`the body such that a front surface of the stopper and the body define a variable
`volume chamber from which a fluid can be expelled though the outlet, the plunger
`comprising a plunger contact surface at a first end and a rod extending between
`the plunger contact surface and a rear portion, the plunger contact surface
`arranged to contact the stopper, such that the plunger can be used to force the
`stopper towards the- outlet end of the body, reducing the volume of the variable
`volume chamber, characterised in that the fluid is an ophthalmic solution which
`comprises a VEGF-antagonist, wherein
`
`(a) the syringe has a nominal maximum fill volume of between about 0.5ml and
`about 1ml,
`
`.r··-··1
`
`Regeneron Exhibit 1002.0389
`
`

`

`23_ 11_2012-01-00003-00000039
`..
`
`"
`
`-16-
`
`(b) the syringe is filled with between about 0.15ml and about 0.175ml of said VEGF
`antagonist solution which comprises a dosage volume of about 0.05ml of said
`VEGF antagonist solution,
`
`(c) the syringe barrel comprises less than about 500µg silicone oil,
`
`(d) the VEGF antagonist solution comprises no more than 2 particles ~50µm in
`diameter per ml, and
`
`(e) the VEGF antagonist is· the antibody VEGF antagonist bevacizumab at a
`concentration of 25 mg/ml.
`
`A pre-filled syringe according to claim 1 or 2, wherein the syringe is filled with
`about 0.165ml of said VEGF antagonist solution.
`
`A pre-filled syringe according to any previous claim, wherein the syringe barrel has
`an internal coating of silicone oil that has an average thickness of about 450nm or
`less.
`
`A pre-filled syringe according to any previous claim, wherein the syringe barrel has
`an internal coating of less than about 500 µg silicone oil, preferably less than about
`1 OOµg silicone oil, preferably less than about SOµg silicone oil, preferably less than
`about 25µg silicone oil.
`
`5
`
`10
`
`15
`
`3.
`
`4.
`
`5.
`
`•
`
`6. · A pre-filled syringe according to any previous claim, wherein the silicone oil is
`DC365 emulsion.
`
`20
`
`7.
`
`A pre-filled syringe according to any previous claim, wherein the syringe is silicone
`oil free.
`
`A pre-filled syringe according to any previous claim, wherein the VEGF antagonist
`solution further comprises one or more of (i) no more than 5 particles ~25µm in
`diameter per ml, and (ii) no more than 50 particles ~1 Oµm in diameter per ml.
`
`25
`
`9.
`
`A pre-filled syringe according to any previous claim, wherein the VEGF antagonist
`solution meets USP789.
`
`10. A pre-filled syringe according to any previous claim, wherein the syringe has a
`stopper break loose force of less than about 11 N.
`
`11. A pre-filled syringe according to claim 10, wherein the syringe has a stopper break
`loose force of less than about SN.
`
`30
`
`12. A pre-filled syringe according to any previous claim, wherein the syringe has a
`stopper slide force of less than about 11 N.
`
`Regeneron Exhibit 1002.0390
`
`

`

`23_11_2012-01-00003-00000040
`
`- -----·- - - - - - - - - - - - - - .
`
`'
`
`- 17 -
`
`13. A pre-filled syringe according to claim 12, wherein the syringe has a stopper slide
`force of less than about SN.
`
`· 14. A pre-filled syringe according to any previous claim, in which the dosage volume is
`determined by volume of the variable volume chamber when a predetermined part
`of the stopper or plunger is aligned with a priming mark on the syringe
`
`5
`
`15. A blister pack comprising a pre-filled syringe according to any previous claim,
`wherein the syringe has been sterilised using H20 2 or EtO.
`
`16. A blister pack comprising a pre-filled syringe according to claim 15, wherein the
`outer surface of the syringe has ~1 ppm EtO or H202 residue.
`
`•
`
`•••
`
`10
`
`17. A blister pack comprising a pre-filled syringe according to claim 15, wherein the
`syringe has been sterilised using EtO or H20 2 and, the total EtO or H20 2 residue
`found on the outside of the syringe and inside of the blister pack is ~0.1 mg ..
`
`i .
`
`18.
`
`A blister pack comprising a pre-filled syringe according to any one of claims 15-17,
`wherein ~5% of the VEGF antagonist is aJkylated.
`
`15
`
`19. A blister pack comprising a pre-filled syringe according to any of claims 15-18,
`wherein the syringe has been sterilised using EtO or hydrogen peroxide with a
`Sterility Assurance Level of at least 10-e.
`
`20.
`
`A kit comprising: (i) a pre-filled syringe according to any one of claims 1-14, or a
`blister pack comprising a pre-filled syringe according to any one of claims 15-19,
`(ii) a needle, and optionally (iii) instructions for administration.
`
`20
`
`21.
`
`A kit according to claim 20, wherein the needle is a 30-gauge x Y:z inch needle.
`
`22 .
`
`A pre-filled syringe according to any one of claims 1-14 for use in therapy.
`
`23.
`
`25
`
`A pre-filled syringe according to any one of claims 1-14 for use in the treatment of
`an ocular disease selected from choroidal neovascularisation, wet age-related
`macular degeneration, macular edema secondary to retinal vein occlusion (RVO)
`including both branch RVO
`(bRVO) and central RVO (cRVO), choroidal
`neovascularisation secondary to pathologic myopia (PM), diabetic macular edema
`(DME), diabetic retinopathy, and proliferative retinopathy.
`
`Regeneron Exhibit 1002.0391
`
`

`

`23 _ 11 _2012-01-00003-00000041
`
`'\.
`tc
`
`"'I
`
`....
`
`/
`
`'-
`
`Fig 1
`
`•
`
`s
`
`1/1
`
`z.
`/
`
`6
`
`/
`""
`
`4.
`
`I
`
`....
`
`I""
`
`\L 3.S
`
`'30
`
`4-2..
`
`16
`
`10
`
`I
`
`Fig4
`
`Fig 5
`
`Regeneron Exhibit 1002.0392
`
`

`

`SCORE Placeholder Sheet for IFW Content
`
`DocCode - SCORE
`
`Application Number: 13750352
`
`Filing Date: 03/15/2013
`
`The presence of this form in the IFW record indicates that the following document is stored
`in the SCORE database
`
`• Certified Copy of Foreign Application with Color Illustrations
`
`To access the documents in the SCORE database, refer to instructions below.
`
`At the time of document entry (noted above):
`• Examiners may access SCORE content via the eDAN interface.
`• Other USPTO employees can bookmark the current SCORE URL
`(http://es/ScoreAccessWeb/).
`• External customers may access SCORE content via the Public and Private
`PAIR interfaces.
`
`Regeneron Exhibit 1002.0393
`
`

`

`BUNDESREPUBLIK DEUTSCHLAND
`
`Prioritatsbeschei n ig u ng
`DE 20 2013 000 688.9
`Ober die Einreichung einer Gebrauchsmusteranmeldung
`
`Aktenzeichen:
`
`20 2013 000 688.9
`
`Anmeldetag:
`
`23.Januar2013
`
`Anmelder/lnhaber:
`
`Novartis AG, Basel, CH
`
`Bezeichnung:
`
`Glas-Spritze
`
`Prioritat:
`
`16.November2012;AU;2012101678
`
`16. November 2012; AU; 2012101677
`
`23. Oktober 2012; EP; 12189649.2
`
`16. November 2012; DE; 20 2012 011 016.0
`
`03. Juli 2012; EP; 12174860.2
`
`03. Dezember 2012; EP; 12195360.8
`
`IPC:
`
`A61F 9/00; A61M 5/178
`
`Die angehefteten Stucke sind eine richtige und genaue Wiedergabe der Teile der
`am 23. Januar 2013 eingereichten Unterlagen dieser Gebrauchsmusteranmeldung
`unabhangig von gegebenenfalls durch das Kopierverfahren bedingten
`Farbabweichungen.
`
`Regeneron Exhibit 1002.0394
`
`

`

`23_01_2013-01-00003-00000106
`
`- 1 -
`
`Beschreibung
`
`GLAS-SPRITZE
`
`TECHNISCHES GEBIET
`
`Die vorliegende Erfindung betrifft eine Spritze, insbesondere eine kleinvolumige Spritze,
`5 die sich zum Verabreichen ophthalmischer lnjektionen eignet.
`
`STAND DERTECHNIK
`
`Patienten werden viele Medikamente mit Hilfe einer Spritze verabreicht. mit der der
`Anwender das Medikament anwenden kann. Wird einem Patienten ein Medikament in
`einer Spritze verabreicht, geschieht dies oft, um es dem Patienten oder einer
`10 Pflegeperson zu ermoglichen, das Medikament selbst zu
`injizieren. Fur die
`Patientensicherheit und die Unversehrtheit des Medikaments ist es wichtig, dass die
`Spritze und deren lnhalte ausreichend steril sind, um lnfektionen und andere Risiken fur
`die Patienten zu vermeiden. Die Sterilisation kann durch eine abschlie~ende Sterilisation
`erreicht werden, bei der das zusammengefugte Produkt, das sich typischerweise bereits
`15 in der dazugehorigen Verpac~ung befindet, unter Zuhilfenahme von Hitze oder eines
`sterilisierenden Gases sterilisiert wird.
`
`Im Fall van kleinvolumigen Spritzen, zum Beispiel jenen fur lnjektionen in das Auge, bei
`denen beabsichtigt ist. dass ungefahr 0, 1 ml oder weniger der Flussigkeit injiziert werden
`sollen, kann die Sterilisation zu Problemen fuhren, die bei gro~ren Spritzen nicht
`20 unbedingt auftreten. Druckveranderungen innerhalb oder au~rhalb der Spritze konnen
`dazu
`fuhren, dass sich Teile der Spritze unvorhersehbar bewegen, was
`Dichteeigenschaften verandern und unter Umstanden die Sterilitat beeintrachtigen kann.
`
`sind bestimmte Therapeutika, wie biologische MolekOle, besonders
`Zudem
`sterilisationsempfindlich, handelt es sich um eine kalte Gassterilisation, eine thermische
`25 Sterilisation oder eine Bestrahlung. Daher ist ein vorsichtiger Balanceakt notwendig, um
`sicherstellen, dass, wahrend ein geeigneter Sterilisationsgrad erreicht wird, die Spritze
`weiterhin entsprechend abgedichtet bleibt, damit das Therapeutikum nicht beeintrachtigt
`wird. Selbstverstandlich muss die Spritze leicht handhabbar bleiben, insofern dass die
`Kraft, die erforderlich ist, um den Kolben herabzudrucken, um das Medikament zu
`30 verabreichen, nicht zu hoch sein darf.
`
`Deshalb besteht ein Bedarf nach einer neuen Spritzenkonstruktion, die eine stabile
`Abdichtung fur ihre lnhalte bietet, aber eine leichte Handhabung beibehalt.
`
`·-~ •..
`
`Regeneron Exhibit 1002.0395
`
`

`

`23_01_2013-01-00~03-00000107
`
`23_0l....2013-0l-uootrd-l300U0l 07
`
`OFFENBARUNG DER ERFINDUNG
`
`-2-
`
`Die vorliegende Erfindung stellt eine vorgefullte Spritze bereit. die Spritze umfasst einen
`Karper, einen Stopper und einem Kolben, ·wobei der Karper an einem Auslass-Ende
`einen Auslass umfasst und der Stopper im Kerper so angeordnet ist, dass die frontale
`5 Oberflache des Stoppers und der Kerper eine Kammer mit variablem Volumen bzw.
`variable Volumenkammer beschreiben, aus der eine FIOssigkeit durch den Auslass
`gedruckt wird, der Kolben umfasst eine Kolbenkontaktflache an einem ersten Ende und
`einen Stab, der sich zwischen der Kolbenkontaktflache und einem hinteren Anteil
`erstreckt, die Kolbenkontaktflache ist derart angeordnet, um den Stopper zu berOhren,
`1 O damit der Kolben dazu benutzt werden kann, den Stopper zum Auslass-Ende des
`Kerpers zu drOcken, wobei das Volumen der Kammer mit variablem Volumen vermindert
`wird, gekennzeichnet dadurch, dass die FIOssigkeit eine ophthalmische Losung umfasst.
`In einer AusfOhrungsform umfasst d